Schizophrenia is a debilitating disorder that affects almost 1% of the world's population. The burden on the families and caregivers of patients is immense, and the cost of care in the U.S. is >$60 billion/y. The high costs arise, in part, due to a lack of innovation that has resulted in very limited, ineffective treatments that are associated with poor compliance. Virtually all of the major antipsychotics approved by the FDA in the past fifty years act primarily on dopamine and/or serotonin receptor function, and unfortunately, these antipsychotics produce severe side effects and are ineffective in treating a number of the symptoms of schizophrenia. The overall goal of this Phase I SBIR is to capitalize on recent advances from the principal investigators laboratories implicating a highly novel mechanism of glutamate release that may contribute to schizophrenia. Specifically, cystine-glutamate exchange appears to be altered in schizophrenic patients, and targeting this mechanism has been shown to be highly effective in a rodent model of schizophrenia. In an effort to test the hypothesis that cystine-glutamate exchange represents an effective treatment target for schizophrenia and other disorders, we will synthesize novel cysteine analogs. Next, we will evaluate the capacity of the new analogs to induce cystine-glutamate exchange in cortical cultures in vitro, and test the most promising compounds for their ability to normalize sensorimotor gating deficits produced by phencyclidine in a rodent model of schizophrenia. The ability to identify therapeutic candidates by this approach will provide addition support for our hypothesis, and establish a basis for pursuing additional pre-clinical and ultimately clinical studies of cystine analogs as treatments for schizophrenia and potentially other psychiatric disorders. PUBLIC HEALTH RELEVANCE: Schizophrenia is a debilitating disorder that results in a devastating burden on the families and caregivers of patients and a cost of care in the U.S. of >$60 billion/year. The high costs arise, in part, due to a lack of innovation that has resulted in very limited, ineffective treatments that are associated with poor compliance due to poor efficacy and the emergence of serious side effects. The primary goal of this Phase I SBIR is to develop novel treatments for schizophrenia.